Regulatory Decision Summary for Imbruvica

Only the highest and lowest strengths of the proposed Imbruvica tablets were tested in comparative bioavailability studies. Based on the biopharmaceutical review, the tablet and capsule at 140 mg strength are bioequivalent. In a similar study comparing 560 mg doses of ibrutinib as either 1 x 560 mg tablets or 4 x 140 mg capsules, AUC_0-t was comparable for the two dosage forms but C_max was 28% lower for Imbruvica 560 mg tablets as compared with the capsules. Justifications for clinical relevance of the lower C_max were provided by the sponsor, which were considered acceptable for the approval of the tablet forms. As the clinical significance of the lower C_max is unknown, the results of the comparative bioavailability studies were included in the Imbruvica product monograph.

In three BA and BE studies, increases in transaminases and/or bilirubin were noted in healthy subjects who were administered the 560 mg Imbruvica. Hepatotoxicity associated with the administration of Imbruvica was reviewed in 2015 in a Notifiable Change submission (control # 187662) and the product labelling was updated to reflect that signal. Following a clarification request, Imbruvica Product Monograph was updated with additional information regarding hepatotoxicity in the Post-Market Adverse Drug Reactions section based on the US Product Information. Janssen Inc. committed to provide an updated report on hepatotoxicity by 4 April 2019 to the Marketed Health Products Directorate. Information regarding the effect of food on Imbruvica exposure, and results of a drug-drug interaction study with a proton pump inhibitor were also added based on this review.

The tablet formulations are expected to reduce pill burden, allowing patients to take the recommended daily dose as a single tablet which is expected to improve patient compliance and convenience. The lower tablet strengths (140 mg and 280 mg) are intended to be used for dosing adjustments in accordance with the product label. Based on this review, the ibrutinib tablets are not associated with additional safety risk. The benefit/risk profile of ibrutinib remains favorable for Imbruvica when used as recommended in the currently approved indications.